Targeting the formation of estrogens for treatment of hormone dependent diseases–current status

Abstract

Local formation and action of estrogens have crucial roles in hormone dependent cancers and benign diseases like endometriosis. Drugs that are currently used for the treatment of these diseases act at the receptor and at the pre-receptor levels, targeting the local formation of estrogens. Since 1980s the local formation of estrogens has been targeted by inhibitors of aromatase that catalyses their formation from androgens. Steroidal and non-steroidal inhibitors have successfully been used to treat postmenopausal breast cancer and have also been evaluated in clinical studies in patients with endometrial, ovarian cancers and endometriosis. Over the past decade also inhibitors of sulfatase that catalyses the hydrolysis of inactive estrogen-sulfates entered clinical trials for treatment of breast, endometrial cancers and endometriosis, with clinical effects observed primarily in breast cancer. More recently, inhibitors of 17beta-hydroxysteroid dehydrogenase 1, an enzyme responsible for formation of the most potent estrogen, estradiol, have shown promising results in preclinical studies and have already entered clinical evaluation for endometriosis. This review aims to provide an overview of the current status of the use of hormonal drugs for the major hormone-dependent diseases. Further, it aims to explain the mechanisms behind the -sometimes- observed weak effects and low therapeutic efficacy of these drugs and the possibilities and the advantages of combined treatments targeting several enzymes in the local estrogen formation, or drugs acting with different therapeutic mechanisms.

Synthesis and Systematic Investigation of Lepidiline A and Its Gold(I), Silver(I), and Copper(I) Complexes Using In Vitro Cancer Models and Multipotent Stem Cells

“…Growth of T-47D was shown to depend on the activity of HSD17B1, , a protein that catalyzes estrogen activation by converting estrone (E1) to estradiol (E2). In theory, susceptibility of this line could be provoked by blocking the function of HSD17B1. , Since LA was suggested to have a binding site on hamster HSD17B1, we performed a preliminary docking experiment, which predicted that LA accommodates in the steroid binding pocket of human HSD17B1 structures (Table S2 and Figure S1). Therefore, the LA binding to the HSD17B1 might cause the elevated sensibility of T-47D cells, but this hypothesis must be supported by further experiments, which is outside of the scope of this paper.…”

The significance of immune microenvironment in patients with endometriosis

“…Furthermore, the endometriotic implants express enzymes, such as aromatase and 17β-hydroxysteroid dehydrogenase type 1, that are involved in estradiol production, and are deficient in 17β-hydroxysteroid dehydrogenase type 2, which normally inactivates estrogen, thus creating a hyperestrogenic milieu [ 47 ]. In endometriotic implants, a cellular resistance to progesterone may further enhance the estradiol effects [ 48 ].…”

A disproportionality analysis of adverse events caused by GnRHas from the FAERS and JADER databases

“…Hormone-dependent diseases also include noncancerous conditions such as precocious puberty, endometriosis, uterine fibroids, Cushing’s syndrome, and polycystic ovarian syndrome (PCOS) ( Zondervan et al, 2020 ; Rižner and Romano, 2023 ). Although these conditions are non-life-threatening, they significantly impact quality of life.…”

“…Hormone-dependent cancers, such as breast and prostate cancers, constitute over 20% of all cancers globally and over 35% of cancers in women ( Sung et al, 2021 ; Rižner and Romano, 2023 ). Imbalances at any level of the hypothalamic–pituitary–gonadal (HPG) axis may lead to various hormone-dependent diseases (HDDs), including precocious puberty, infertility, hormone-dependent cancers, polycystic ovarian syndrome, endometriosis, and uterine fibroids ( Newton et al, 2018 ).…”